Exposure to psychostimulants such as cocaine and amphetamine causes behavioral changes including addiction and dependence. Addiction is defined by compulsive drug taking and may involve abnormal motor learning/habit formation, a function that has been ascribed to dorsal parts of the striatum. Motor learning likely involves modification of synaptic connections and altered gene regulation. Many studies have shown that psychostimulants produce changes in the expression of various genes, including genes that encode transcription factors, structural proteins and signaling molecules. Moreover, such gene regulation preferentially occurs in dorsal striatal sectors that are part of "motor" loops that interconnect the cortex and the basal ganglia. Neuronal changes related to motor learning/habit formation would be expected to be triggered during (or in close association with) motor performance and be related to such performance. The experiments of the present proposal will investigate whether the behavior performed during the influence of cocaine can modify neuronal changes produced by cocaine. Thus, we propose to test the hypothesis that different behaviors during cocaine action will be associated with different changes in gene expression in striatal neurons. Differential "behavioral treatment" will consist of repeated exposure to a running wheel vs. a small open field immediately after the cocaine injection. In situ hybridization histochemistry will be used to compare changes in gene expression in various striatal sectors between such differentially treated rats. Initially, a short-term molecular marker (c-fos induction by a cocaine challenge) and longer-term markers (neuropeptides such as dynorphin) will be assessed. As a first step to determine behavioral effects, open-field behavior induced by a cocaine or vehicle challenge will be examined subsequent to the repeated treatments. These studies should provide new insights into how the behavior executed during the drug action can influence drug-induced neuroplasticity in the striaturn.